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1.
Invest Ophthalmol Vis Sci ; 61(5): 34, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32433759

RESUMO

Purpose: To examine the biomechanical effects-induced wave-front aberrations after conventional laser refractive surgery. Methods: A finite element model of the human eye was established to simulate conventional laser refractive surgery with corrected refraction from -1 to -15 diopters (D). The deformation of the anterior and posterior corneal surfaces was obtained under the intraocular pressure (IOP). Then, the surface displacement was converted to wave-front aberrations. Results: Following conventional refractive surgery, significant deformation of the anterior and posterior corneal surfaces occurred because of the corneal biomechanical effects, resulting in increased residual wave-front aberrations. Deformation of the anterior surface resulted in a hyperopic shift, which was significantly increased with the increasing refractive correction. The residual high-order aberrations consisted of spherical aberration, vertical coma, and y-trefoil. Spherical aberration was significantly positively correlated to enhanced refraction correction. The effect of posterior corneal surface on induced wave-front aberration was less than the anterior corneal surface. The IOP slightly affects the postoperative defocus, coma, and spherical aberration. When treatment decentration occurred during the procedure, the hyperopic shift decreased as the eccentricity increased. Treatment decentration had a significant impact on the spherical aberration and the coma. In addition, the ocular tissue elasticity played a key role in hyperopic shift, whereas it had little effect on the other aberrations. Conclusions: Among the many factors that affect high-order aberrations after conventional laser refractive surgery, the alterations in corneal morphology caused by biomechanical effects must be considered, as they can lead to an increase in postoperative residual wave-front aberrations.

2.
Int J Biol Macromol ; 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32446896

RESUMO

We had observed in our previous study that the active fucoidan (JHCF4), isolated from the crude fucoidan in acid-processed Hizikia fusiforme, possessed an anticancer effect. In this study, the antioxidant effect of JHCF4 was evaluated. Among the fractions, JHCF4 showed the highest scavenging activity against 2, 2-diphenyl-1-picrylhydrazyl (DPPH), alkyl, and hydroxyl radicals, as well as protective effect against reactive oxygen species (ROS) in 2, 2'-azobis (2-amidinopropane) dihydrochloride (AAPH)-treated Vero cells. Furthermore, JHCF4 showed a protective activity against AAPH-induced apoptosis, as observed by nuclear staining with Hoechst 33342. Our results showed that JHCF4 can up-regulate Bcl-xL, down-regulate Bax and cleave caspase-3 with increased concentrations in AAPH-induced Vero cells. JHCF4 induced anti-apoptosis via a mitochondria-mediated pathway. Additionally, JHCF4 was selected for further in vivo screening in a zebrafish model, which markedly decreased ROS generation and lipid peroxidation. Thus, JHCF4 showed a potential protective activity against AAPH-induced ROS both in vitro and in the zebrafish model.

3.
J Diabetes Res ; 2020: 9787839, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32309450

RESUMO

Purpose: Pancreatic stone protein/regenerating protein I (PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG I. Methods: This cross-sectional study was conducted at Zhongda Hospital, affiliated with Southeast University in China. Serum PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG I. Results: Serum PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG IP < 0.05). The level of PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG I. Conclusions: Serum PSP/REG Iα level is significantly upregulated in T2DM patients and reflects renal function in both T2DM and nondiabetic control groups. The relationship between PSP/REG Iα and eGFR suggested that PSP/REG Iα might be a potential indicator of renal dysfunction.α) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG Iα) is a secretory protein mainly detected in the pancreas. Recent studies revealed increased serum PSP/REG I.

4.
J Cell Mol Med ; 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32337851

RESUMO

Myelodysplastic syndrome (MDS) is clonal disease featured by ineffective haematopoiesis and potential progression into acute myeloid leukaemia (AML). At present, the risk stratification and prognosis of MDS need to be further optimized. A prognostic model was constructed by the least absolute shrinkage and selection operator (LASSO) regression analysis for MDS patients based on the identified metabolic gene panel in training cohort, followed by external validation in an independent cohort. The patients with lower risk had better prognosis than patients with higher risk. The constructed model was verified as an independent prognostic factor for MDS patients with hazard ratios of 3.721 (1.814-7.630) and 2.047 (1.013-4.138) in the training cohort and validation cohort, respectively. The AUC of 3-year overall survival was 0.846 and 0.743 in the training cohort and validation cohort, respectively. The high-risk score was significantly related to other clinical prognostic characteristics, including higher bone marrow blast cells and lower absolute neutrophil count. Moreover, gene set enrichment analyses (GSEA) showed several significantly enriched pathways, with potential indication of the pathogenesis. In this study, we identified a novel stable metabolic panel, which might not only reveal the dysregulated metabolic microenvironment, but can be used to predict the prognosis of MDS.

5.
World Neurosurg ; 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32251812

RESUMO

BACKGROUND: Subsidence is an incapacitating complication in anterior cervical discectomy and fusion (ACDF). However, the debate over which of the intervertebral devices is associated with lower incidence of subsidence remains to be settled. METHODS: Seven dominant techniques comprising cage with plate (CP), iliac bone graft with plate (IP), Zero-profile cage with screws (Zero-P), ROI-C cages with clips (ROI-C), polyether ether ketone cage alone (PCA), iliac crest autogenous graft (ICAG), and titanium cage alone (TCA) were examined. The incidences of subsidence in the different groups were calculated and compared. RESULTS: A total of 30 studies with 2264 patients were identified. Overall, the CP group presented the lowest incidence of subsidence, and its incidence was significantly lower than that in the Zero-P group, the PCA group, the ICAG group, and the TCA group (P < 0.05). The incidence of subsidence in the IP group was significantly lower than that in the PCA group, the ICAG group, and the TCA group (P < 0.05). In single-level ACDF, the CP group presented the lowest incidence of subsidence, and its incidence was significantly lower than that in the PCA group and the TCA group (P < 0.05). No difference was found between single-level and multilevel ACDF and the incidence of subsidence was higher in those undergoing single-level ACDF. CONCLUSIONS: CP and IP resulted in a lower rate of subsidence than cage alone or ICAG. Zero-P and ROI-C cages led to similar subsidence rates with plate. All types of intervertebral device can be applied to both single-level and multilevel ACDF with comparable subsidence rate.

6.
Med Sci Monit ; 26: e921430, 2020 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-32304567

RESUMO

BACKGROUND Squamous cell lung cancer is the main cause of cancer-associated mortality. The discovery of promising prognostic biomarkers for predicting the survival of patients with squamous cell lung cancer remains a challenge. MATERIAL AND METHODS Gene expression profiles of GSE33479 and GSE51855, including 42 squamous cell lung cancer tissues and 17 normal tissues, from the GEO database were assessed to find common differentially expressed genes (DEGs) via the GEO2R online tool and Venn diagram software. Then, gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses were conducted. The key protein-protein interaction (PPI) network within those common DEGs was subsequently illustrated through a combination of Search Tool for Retrieval of Interacting Genes (STRING) and Cytoscape software. Finally, core genes associated with survival and levels of immune infiltration were demonstrated by the Kaplan-Meier plotter and Tumor Immune Estimation Resource (TIMER) online database, respectively. RESULTS In total, 483 DEGs were involved, including 216 upregulated genes enriched in "cell division", "DNA replication", and "DNA repair pathway" and 267 downregulated genes enriched in "cell adhesion", "oxidation-reduction process", and "cell-cell signaling". The 75 core genes were selected by Molecular Complex Detection applied in Cytoscape. Four genes - MND1, FOXM1, CDC6, and POLE2 - were found to be significantly associated with survival. Further analysis of the KEEG pathway and TIMER database revealed that only POLE2 was enriched in "DNA replication" and its higher expression was negatively associated with survival and immune infiltration. CONCLUSIONS Higher expression of POLE2 is a prognosis-related biomarker for worse survival and is negatively associated with immune infiltration in squamous cell lung cancer.

7.
Cancer Med ; 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32311840

RESUMO

Cancer stem cells (CSCs) are characterized by self-renewal and -differential potential as compared to common cancer cells and play an important role in the development and therapeutic resistance of liver hepatocellular carcinoma (LIHC). However, the specific pathogenesis of LIHC stem cells is still unclear, and the genes involved in the stemness of LIHC stem cells are currently unknown. In this study, we investigated novel biomarkers associated with LIHC and explored the expression characteristics of stem cell-related genes in LIHC. We found that mRNA expression-based stemness index (mRNAsi) was significantly overexpressed in liver cancer tissues. Further, mRNAsi expression in LIHC increased with the tumor pathological grade, with grade 4 tumors harboring the greatest stem cell features. Upon establishing mRNAsi scores based on mRNA expression of every gene, we found an association with poor overall survival in LIHC. Moreover, modules of interest were determined based on weighted gene co-expression network analysis (WGCNA) inclusion criteria, and three significant modules (red, green, and brown) and 21 key genes (DCN, ECM1, HAND2, PTGIS, SFRP1, SRPX, COLEC10, GRP182, ADAMTS7, CD200, CDH11, COL8A1, FAP, LZTS1, MAP1B, NAV1, NOTCH3, OLFML2A, PRR16, TMEM119, and VCAN) were identified. Functional analysis of these 21 genes demonstrated their enrichment in pathways involved in angiogenesis, negative regulation of DNA-binding transcription factor activity, apoptosis, and autophagy. Causal relationship with proteins indicated that the Wnt, Notch, and Hypoxia pathways are closely related to LIHC tumorigenesis. To our knowledge, this is the first report of a novel CSC biomarker, mRNAsi, to predict the prognosis of LIHC. Further, we identified 21 key genes through mRNA expression network analysis, which could be potential therapeutic targets to inhibit the stemness of cancer cells in LIHC.

8.
Neural Plast ; 2020: 7409417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256558

RESUMO

Purpose: Acupuncture is an effective therapy for Internet addiction (IA). However, the underlying mechanisms of acupuncture in relieving compulsive Internet use remain unknown. Neuroimaging studies have demonstrated the role of the ventral striatum (VS) in the progress of IA; hence, the aim of this study was to explore the effects of acupuncture on the resting-state functional connectivity (rsFC) and relevant network of VS in IA. Methods: Twenty-seven IA individuals and 30 demographically matched healthy control subjects (HCs) were recruited in this study. We acquired the functional magnetic resonance imaging (fMRI) data in IA subjects before and after 40 days of acupuncture treatment. Seed-to-voxel and ROI-to-ROI analyses were applied to detect the rsFC alterations of the VS and related network in IA subjects and to investigate the modulation effect of acupuncture on the rsFC. Results: Compared with HCs, IA subjects exhibited enhanced rsFC of the right ventral rostral putamen (VRP) with the left orbitofrontal cortex (OFC), premotor cortex (PMC), cerebellum, and right ventromedial prefrontal cortex (vmPFC). In the network including these five ROIs, IA also showed increased ROI-to-ROI rsFC. Using a paired t-test in IA subjects before and after 40 days of acupuncture, the increased ROI-to-ROI rsFC was decreased (normalized to HC) with acupuncture, including the rsFC of the right VRP with the left OFC, PMC, and cerebellum, and the rsFC of the left cerebellum with the left OFC, PMC, and right vmPFC. Furthermore, the change in rsFC strength between the right VRP and left cerebellum in IA individuals was found positively correlated with the Internet craving alleviation after acupuncture. Conclusions: These findings verified the modulation effect of acupuncture on functional connectivity of reward and habit systems related to the VS in IA individuals, which might partly represent the underlying mechanisms of acupuncture on IA.

9.
Fitoterapia ; 143: 104549, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32173420

RESUMO

Eight new flavonoids daemoflavans A-H, including two dimeric proanthocyanidins (1 and 2), four flavans (3-6), two 2-arylbenzofurans (7 and 8), along with nine known compounds (9-17), were isolated from the fruit of Daemonorops draco. Their structures, including the absolute configurations, were elucidated by extensive spectroscopic data, ECD analysis, and X-ray crystal diffraction. Besides, the X-ray crystal data of a known compound dracoflavan B1 (9) was firstly reported. Daemoflavan G (7) represents a rare example of C-5 methylated 2-arylbenzofuran in natural products. Among the known compounds, 15, 16, 17 were reported from this species for the first time. All the compounds were evaluated for their cytotoxicity against HepG2 cell line. Among them, compounds 1, 9 and 10 exhibited modest cytotoxic activity with IC50 values of 12.4, 12.0 and 13.2 µM, respectively.

10.
Endocrine ; 2020 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-32147773

RESUMO

PURPOSE: This study aimed to explore the association between low-frequency and rare variants of Wnt signaling genes and postmenopausal osteoporosis (OP) by the next generation sequencing (NGS) technology. METHODS: We performed targeted NGS of nine Wnt signaling genes in 400 Chinese postmenopausal women, including 226 cases with decreased bone mineral density (BMD) and 174 controls with normal values. Proxy External Controls Association Test (ProxECAT) and logistic regression analysis were performed by data from internal cases (n = 226) and Genome Aggregation Database (gnomAD) East Asian controls (n = 9435). RESULTS: The genomic region of interest (ROI) of 94 functional low-frequency and rare variants was associated with OP risk (P < 0.05). The LGR6 gene was associated significantly with OP risk and BMD measurements (BMD, T-score and Z-score) (adjusted-P < 0.05) after adjusting for confounders. The allele A of rs199693693 (K82N) in LRP6 and G of novel variant 1: 202287949 (R840G) in LGR6 were associated with higher BMD, T-score, and Z-score (all adjusted-P < 0.05). ProxECAT showed that LGR4 was significantly different between the internal cases and the external controls (all adjusted-P < 0.05). Logistic regression analysis revealed that the allele G of rs765778410 (T645A) (OR = 26.16, 95% CI: 4.36-156.95, adjusted-P value = 0.026) in LGR6 and A of rs61370283 (L987M) (OR = 15.39, 95% CI: 2.98-79.55, adjusted-P value = 0.037) in LRP5 were associated with increased risk of postmenopausal OP. CONCLUSION: The LGR4 and LGR6 genes and four potential functional rare variants associate with postmenopausal OP risk. These results highlight the significance of rare functional variants in postmenopausal OP genetics and provide new insights into the potential mutations in this field.

11.
Cancer Cell ; 37(3): 403-419.e6, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32183952

RESUMO

Natural killer/T cell lymphoma (NKTCL) is an aggressive and heterogeneous entity of non-Hodgkin lymphoma, strongly associated with Epstein-Barr virus (EBV) infection. To identify molecular subtypes of NKTCL based on genomic structural alterations and EBV sequences, we performed multi-omics study on 128 biopsy samples of newly diagnosed NKTCL and defined three prominent subtypes, which differ significantly in cell of origin, EBV gene expression, transcriptional signatures, and responses to asparaginase-based regimens and targeted therapy. Our findings thus identify molecular networks of EBV-associated pathogenesis and suggest potential clinical strategies on NKTCL.

12.
Acta Biochim Biophys Sin (Shanghai) ; 52(4): 371-381, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32188965

RESUMO

As a subtype of non-small-cell lung cancer, lung squamous cell carcinoma (LUSC) accounts for one-fifth of all lung cancers. Unfortunately, no specific targetable aberration has yet been identified. Hence, it is of huge urgency and potential to identify aberrantly regulated genes in LUSC. Here, five pairs of LUSC samples and their corresponding adjacent tissues were subject to whole transcriptome sequencing. Our results showed that CTD-2562J17.6 and FENDRR were significantly downregulated while MIR205HG, LNC_000378, RP11-116G8.5, RP3-523K23.2, and RP5-968D22.1 were significantly upregulated in all five LUSC samples. Importantly, MIR205HG was upregulated in LUSC clinical samples as well as in LUSC cell lines. Interestingly, our results demonstrated that the expression level of MIR205HG is positively correlated with the malignancy. In addition, MIR205HG is required for LUSC cell growth and cell migration. Most importantly, our results showed that MIR205HG prohibits LUSC apoptosis via regulating Bcl-2 and Bax. Taken together, our data shed lights on the lncRNA regulatory nexus that controls the carcinogenesis of LUSC and provided potential novel diagnostic markers and therapeutic targets for LUSC.

13.
Poult Sci ; 99(2): 1117-1123, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32029147

RESUMO

Colibacillosis, caused by Escherichia coli, is one of the most common bacterial diseases of chickens. The high incidence and considerable economic losses associated with colibacillosis make it a significant concern worldwide. In recent years, the efficacy of colistin has been severely impacted by the emergence of plasmid-mediated colistin resistance genes, especially mcr-1. Therefore, monitoring of antibiotic resistance, particularly colistin resistance, amongst E. coli strains is vitally important to the future growth and sustainability of the poultry industry. In this study, a total of 130 E. coli strains were isolated from the livers of chickens displaying symptoms of colibacillosis in Tai'an, China. Isolates were screened for their susceptibility to various antibiotics and for the presence of mobile colistin resistance genes and other antibiotic resistance genes. Overall, 75 (57.7%) isolates showed resistance to colistin and were positive for mcr-1. The mobile colistin resistance genes, mcr-2, -3, and -4, were not detected in this study. Of the 75 mcr-1-positive isolates, all (100%) also carried tetracycline resistance genes, 71 (94.7%) also contained genes associated with ß-lactam resistance, 59 (78.7%) contained aminoglycoside resistance genes, and 57 (76%) contained sulfonamide resistance genes. This high prevalence of multidrug resistance among mcr-1-positive E. coli isolates, including the production of extended-spectrum ß-lactamases, is highly concerning. The surveillance findings presented here will be conducive to our understanding of the prevalence and characteristics of multidrug-resistance in E. coli in the Tai'an area and will provide a better scientific basis for the clinical treatment of colibacillosis in chickens.

14.
J Sex Med ; 17(4): 614-622, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32037229

RESUMO

BACKGROUND: Although abnormal sympathetic nerve system (SNS) activity has been demonstrated in the pathogenesis of ejaculation disorders, few data are available on its underlying mechanism. AIM: To investigate whether differences in ejaculatory behavior of rats were associated with the state of SNS activity and gamma-aminobutyric (GABA) receptor expressions in the paraventricular nucleus (PVN) of the hypothalamus and the effects of GABA receptors in the PVN on ejaculatory behavior. METHODS: Based on ejaculatory performance, Sprague-Dawley rats were divided into "sluggish," "normal," and "rapid" ejaculators. PVN microinjection was performed to evaluate the role of GABA receptors on sexual behavior. OUTCOMES: The outcomes include differences in expression and distribution of GABA receptors and norepinephrine level among the 3 groups and changes in copulation behavior parameters after PVN microinjection. RESULTS: Compared with "normal" rats, the "rapid" group ejaculated more times with shorter latency (P < .001, P < .001) and had lower expression and distribution of both GABA-A and GABA-B receptors, while the opposed results appeared in the "sluggish" group. The norepinephrine level was successively increased among "sluggish," "normal," and "rapid" rats (P < .001) and correlated with ejaculation frequency (r = 0.896, P < .001) and ejaculation latency (r = -0.835, P < .001). In addition, bilateral microinjection of the GABA-A and GABA-B receptor agonist (isoguvacine and baclofen) into the PVN both significantly prolonged the intromission latency and inhibited ejaculation, which could be blocked by antagonist gabazine and CGP-35348, respectively. Vigabatrin, the GABA-transaminase inhibitor, caused a significantly reduced ejaculation frequency and extended ejaculation latency in rats, which could be offset by simultaneous injections of gabazine and CGP-35348. CLINICAL IMPLICATIONS: Our findings provide new understanding about GABA receptors in the PVN on sexual behavior and enhance the comprehension of neurobiological mechanisms involved in premature ejaculation. STRENGTHS & LIMITATIONS: Our results have indicated that GABA receptors in the PVN may inhibit ejaculation through restraining the activity of SNS. However, our study did not analyze the changes of GABA receptors in other brain areas, which needs further study. CONCLUSION: Ejaculation behaviors in male rats are associated with SNS activity and could be regulated by GABA receptors in the PVN, which may be of assistance in the treatment of ejaculation disorders in the future. Zhang QJ, Yang BB, Yang J, et al. Inhibitory Role of Gamma-Aminobutyric Receptors in Paraventricular Nucleus on Ejaculatory Responses in Rats. J Sex Med 2020;17:614-622.

15.
Nanoscale ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068223

RESUMO

Fabricating lanthanide doped up-conversion luminescence based nanocomposites has drawn increasing attention in nanoscience and nanotechnology. Although challenging in precise synthesis, structure manipulation and interfacial engineering, fabricating dendritic mesoporous silica coated up-conversion nanoparticles (UCNP@dMSNs) with a tunable pore size is of great importance for the functionalization and application of UCNPs. Herein, we report a strategy to prepare uniform monodisperse UCNP@dMSNs with a core-shell structure. The silica shell has tunable center-radial and dendritic mesoporous channels. The synthesis was carried out in the heterogeneous oil-water microemulsion phase of the Winsor III system reaction system, which allows silica to be deposited directly on hydrophobic UCNPs through the self-anchoring of micelle complexes on the oleic acid ligand. The average pore size of UCNP@dMSNs could be tailored from ∼10 to ∼35 nm according to the varied amounts of co-solvent in the mixture. The microemulsion approach could also be used to prepare hierarchical UCNP@dMSNs with a multi-generational mesostructure. The resultant UCNP@dMSNs exhibit the unique advantage of loading "guest" nanoparticles in a self-absorption manner. We proved that Cu1.8S NPs (∼10 nm), Au NPs (∼10 nm) and Fe3O4 NPs (∼25 nm) could be incorporated in UCNP@dMSNs, which in turn validates the high adsorption capacity of UCNP@dMSNs.

16.
Drug Deliv Transl Res ; 10(1): 122-135, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31444736

RESUMO

PEGylated triacontanol (mPEG2k-b-TRIA) was developed as a dual-functional polymer with remarkable biocompatibility. The polymer could self-assemble to micelles with critical micelle concentration (CMC) 17.62 µg mL-1. Docetaxel-loaded mPEG2k-b-TRIA micelles (DTX PMs) were fabricated to evaluate the feasibility of mPEG2k-b-TRIA as drug delivery system. DTX PMs achieved desirable particle size of 93.7 nm, drug loading of 6.66%, and drug encapsulation efficiency of 89.87%. The drug release was based on first-order kinetics model, thus enabling prolonged release. Meanwhile, pharmacokinetic study also revealed that DTX PMs could improve the exposure level of DTX and prolong its systemic circulation time. Furthermore, DTX PMs demonstrated significantly enhanced cytotoxicity and cellular uptake in vitro compared with DTX solution. The in vivo tumor inhibition study carried out on MCF-7 bearing BALB/c mice model also validated that DTX PMs exhibited stronger anti-tumor activity but low toxicity. Notably, mPEG2k-b-TRIA made some contribution to inhibit the growth of breast cancer cells in vitro and in vivo, indicating the potential as anti-tumor complementary agents. All the results suggested that mPEG2k-b-TRIA polymer as a vehicle in the formulation of anti-cancer drugs may provide an effective way to improve their therapeutic efficacy. Consequently, the mPEG2k-b-TRIA polymers would be another promising carrier for hydrophobic anti-cancer drugs delivery.

17.
Arch Toxicol ; 94(1): 231-244, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31740989

RESUMO

Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave's disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography-tandem mass spectrometry (GC-MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6, which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.

18.
Eur J Pharmacol ; 869: 172802, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31738930

RESUMO

The paraventricular nucleus of the hypothalamus (PVN) contains dense orexin 2 (OX2) receptor. We examined the mechanisms of OX2 receptor-mediated excitation on electrophysiologically identified type I (putative magnocellular), low-threshold spikes (LTS)-expressing type II (putative preautonomic), and non-LTS type II (putative parvocellular neuroendocrine) neurons. In the presence of tetrodotoxin, an OX2 receptor agonist, ALOXB (30-1000 nM) depolarized 56% of type I, and 73-75% of type II neurons. In type I neurons, ALOXB-induced inward current displayed increased-conductance current-voltage (I-V) relationship and reversed polarity at -27.5 ± 4.8 mV. A Na+-Ca2+ exchanger (NCX) inhibitor, KBR-7943, attenuated ALOXB responses in the majority of type I neurons, while no attenuation was observed in nearly all type II neurons. Type II neurons exhibited three types of I-V relationships in response to ALOXB, characterized by decreased, increased, and unchanged conductance, respectively. The reversal potential of the decreased-conductance responses was near the equilibrium potential of K+ (Ek+) and became more positive in a high-K+ solution, suggesting that K+ conductance blockade is involved. In a low-Na+ solution, non-reversed I-V curves of increased-conductance responses became decreased-conductance responses and reversed polarity near Ek+, suggesting the involvement of both K+ conductance and non-selective cation conductance (NSCC). Approximately 35% of LTS-expressing type II neurons were vasopressin-immunoreactive and 71% of them responded to ALOXB. In conclusion, orexins may activate OX2 receptor on PVN neurons and cause depolarization by promoting NCX and/or NSCC in magnocellular neurons, and by decreasing K+ conductance and/or increasing NSCC in parvocellular neurons. Furthermore, the majority of vasopressinergic preautonomic neurons are under OX2 receptor regulation.

19.
Chemistry ; 26(8): 1819-1826, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808197

RESUMO

The fabrication of advanced graphene-based nanocomposites with high-performance polymers requires covalent modification of graphene with aromatic macromolecules. Herein, C-N coupling reactions between fluorinated graphene (FG) and aromatic polyamides containing the benzimidazole moiety are successfully achieved. The optimized conditions are presented based on the nucleophilic behavior of the C-N coupling reaction on graphene. Different from the C-N coupling reaction between two small aromatic molecules, the conformation of grafted aromatic polyamide after reaction changes from torsional to paralleled alignment on graphene with the molecular length increment. Non-covalent interactions between graphene and aromatic polyamides result in this conformational change owing to the extended π systems of graphene and aromatic polyamides, and the synergistic effect of covalent and non-covalent interactions is put forward. As a consequence, graphene dispersibility is greatly enhanced in the solution of aromatic polyamide.

20.
J Virol ; 94(3)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31694953

RESUMO

Epstein-Barr virus (EBV) genomic DNA is replicated and packaged into procapsids in the nucleus to form nucleocapsids, which are then transported into the cytoplasm for tegumentation and final maturation. The process is facilitated by the coordination of the viral nuclear egress complex (NEC), which consists of BFLF2 and BFRF1. By expression alone, BFLF2 is distributed mainly in the nucleus. However, it colocalizes with BFRF1 at the nuclear rim and in cytoplasmic nuclear envelope-derived vesicles in coexpressing cells, suggesting temporal control of the interaction between BFLF2 and BFRF1 is critical for their proper function. The N-terminal sequence of BFLF2 is less conserved than that of alpha- and betaherpesvirus homologs. Here, we found that BFLF2 amino acids (aa) 2 to 102 are required for both nuclear targeting and its interaction with BFRF1. Coimmunoprecipitation and confocal analysis indicated that aa 82 to 106 of BFLF2 are important for its interaction with BFRF1. Three crucial amino acids (R47, K50, and R52) and several noncontinuous arginine and histidine residues within aa 59 to 80 function together as a noncanonical nuclear localization signal (NLS), which can be transferred onto yellow fluorescent protein (YFP)-LacZ for nuclear targeting in an importin ß-dependent manner. Virion secretion is defective in 293 cells harboring a BFLF2 knockout EBV bacmid upon lytic induction and is restored by trans-complementation of wild-type BFLF2, but not NLS or BFRF1-interacting defective mutants. In addition, multiple domains of BFRF1 were found to bind BFLF2, suggesting multiple contact regions within BFRF1 and BFLF2 are required for proper nuclear egress of EBV nucleocapsids.IMPORTANCE Although Epstein-Barr virus (EBV) BFRF1 and BFLF2 are homologs of conserved viral nuclear egress complex (NEC) in all human herpesviruses, unique amino acid sequences and functions were identified in both proteins. In this study, the nuclear targeting and BFRF1-interacting domains were found within the N terminus of BFLF2. We showed that amino acids (aa) 82 to 106 are the major region required for BFLF2 to interact with BFRF1. However, the coimmunoprecipitation (Co-IP) data and glutathione transferase (GST) pulldown experiments revealed that multiple regions of both proteins contribute to reciprocal interactions. Different from the canonical nuclear localization signal (NLS) in other herpes viral homologs, BFLF2 contains a novel importin-dependent nuclear localization signal, including R47, K50, and R52 and several neighboring discontinuous arginine and histidine residues. Using a bacmid complementation system, we show that both the nuclear targeting and the novel nuclear localization signal within aa 82 to 106 of BFLF2 are required for virion secretion.

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